We have analyzed high-resolution chromosomes of lymphomatous cells from 100 patients with non-Hodgkin's lymphoma and found that 93% of them have a chromosomal defect and two-thirds have one of six specific chromosome defects. Some histologic types often showed specific recurrent defects. Diffuse large cell lymphoma was found to represent a heterogeneous group of disorders with either a deletion 6q, a t(8;14), a t(11;14), or a t(14;18). The t(14;18) that we have found exclusively in lymphomas of follicular origin appears to confer a more favorable prognosis upon those patients who have the defect, compared to those who have a follicular lymphoma without the defect. In small lymphocytic cell lymphoma, patients often show a trisomy 12 or a defect in chromosome 11, usually a t(11;14)(q13.3;q32) or a deletion 11(q14; q23). Patients with a deletion 11q may have a more aggressive clinical course requiring more intensive treatment. Besides chromosome defects of diagnostic and prognostic significance, 16 heritable chromosomal fragile sites (fra) have been defined. We have found that fra 6p23, 8q22.1, 9p21, 11q13.3, 11q23.3, 12q13.1, 16p12.3, and 16q22.1 are localized at or near the breakpoint of one of the two inversions and six of the 13 specific translocations found in leukemias and non-Hodgkin's lymphomas. We have also found a fra 11q13.3 in the normal blood cells of two out of two patients with small lymphocytic cell lymphoma and t(11;14)(q13.3;q32.3); a fra 12q13.1 in a patient with diffuse mixed T-cell lymphoma with t(12;14)(q13.1;q32.3); a fra 8q22.1 (where the oncogene c-mos has been mapped) in two of two patients with ANLL-M2 and t(8;21)(q22.1;q22.3) in their leukemic marrow cells; and a fra 16q22.1 in the normal cells of five of six patients with acute myelomonocytic leukemia and an inv(16)(p13.1;q22.1). Confirmation of these findings would suggest that some individuals could be genetically predisposed to develop certain malignancies and that a blood test could be developed for screening them. Finally, in collaboration with Dr. Carlo Croce's group, we have shown that a transcribed DNA sequence, bcl-1, is normally located in band 11q13.3 (fragile site band) and rearranges with the IgH locus of chromosome 14 in the t(11;14) (q13.3;q32.3) found in small lymphocytic cell lymphoma. In the t(14;18)(q32.3;q21.3) of follicular lymphomas, putative oncogenes from 18q21.3 (bcl-2) were also found rearranged with chromosome 14. These represent the first examples of previously unknown oncogenes discovered via chromosomal rearrangements and represent one-third of all non-Hodgkin's lymphomas. (K)